Stereoselective hydrogenation of a ketone

ABSTRACT

The present invention relates to a method comprising reducing a ketone of formula I: 
     
       
         
         
             
             
         
       
     
     with an enantioselective hydrogenating agent to form substantially enantiomerically pure alcohol of formula II: 
     
       
         
         
             
             
         
       
     
     where R—R 4  and m are as defined herein. The method of the present invention is useful for making CCR2 modulators as wells as precursors CCR2 modulators.

BACKGROUND OF THE INVENTION

The present invention relates to a method of stereoselectively hydrogenating a ketone that is particularly useful as an intermediate for a CCR2 antagonist.

CCR2 is a chemokine receptor that is expressed on a cell surface of monocycles and some other blood leukocytes. CCR2 binds to the monocyte chemotactic protein MCP-1, and other CC chemokines, which are produced at sites of inflammation and infection. Recruitment of monocytes to inflammatory sites by MCP-1/CCR2 interactions has been implicated in driving the pathogenesis of a number of diseases including multiple inflammatory disorders including rheumatoid arthritis, atherosclerosis, multiple sclerosis, bronchiolitis obliterans syndrome, asthma, allergic rhinitis, eczema, atopic dermatitis, kidney disease, alveolitis, nephritis, liver cirrhosis, congestive heart failure, viral meningitis, cerebral infarction, neuropathy, Kawasaki disease, Alzheimer's disease, stroke, acute nerve injury, HIV infection, AIDS, autoimmune diseases, cancer, sepsis, retinosis, inflammatory bowel disease, transplant arteriosclerosis, idiopathic pulmonary fibrosis, psoriasis, HIV-associated dementia, lupus, erthematosis, hepatitis, pancreatitis, Crohn's disease, endometriosis, metabolic syndrome, and diabetes.

A number of compounds in the art described as CCR2 antagonists contain a chiral hydroxyethylene group that links two piperidinyl groups. For example, US 2008/0318990 discloses CCR2 modulators that contain the following 1S enantiomeric fragment:

It would be desirable to discover a new way to prepare these chiral molecules.

SUMMARY OF THE INVENTION

The present invention relates to a method comprising reducing a ketone of formula I:

with an enantioselective hydrogenating agent to form a substantially enantiomerically pure alcohol of formula II:

wherein R is H or OH; R¹ is H, an amine protecting group,

each R² is independently halo, methyl, hydroxy, or hydroxymethyl; R³ is H and R⁴ is phenyl-(R⁵)_(n), indolyl-(R⁸)_(p), 1-H-pyrrolo[2,3-b]pyridine-3-yl-(R⁸)_(p), benzimidazolyl-(R⁸)_(p), benzoxazolyl-(R⁸)_(p), or pyrazolyl; or R³ and R⁴, together with the carbon atom to which they are attached form a spiroindolinyl, a spiroindanyl, a spiroindenyl, or a spirodihydrobenzoxazolyl group, each optionally substituted with up to three substituents selected from the group consisting of halo, CN, C₁-C₆-alkyl, C₁-C₆-alkoxy, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, SO₂CH₃, (R⁵)_(n)-phenoxy-, (R⁵)_(n)-benzyloxy-, C(O)N(R⁹)₂, and COOH; each R⁵ is independently halo, CN, C₁-C₆-alkyl, C₁-C₆-alkoxy, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, SO₂CH₃, phenyl, C(O)N(R⁹)₂, or COOH; R⁶ and R⁷ are each independently H, C₁-C₆ alkyl, phenyl-(R⁵)_(n), heteroaryl-(R⁸)_(p), CON(R⁹)₂, CN, COOH, COOCH₃, COOCH₂CH₃, or R⁶ and R⁷, together with the carbon atoms to which they are attached, form a fused benzo group; each R⁸ is independently halo, amino, cyano, C₁-C₆-alkyl, C₁-C₆-alkoxy, —NHSO₂CH₃, —NHC(O)CH₃, C₅-C₆-heterocycloalkyl, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, SO₂CH₃, C(O)N(R¹⁰)₂, (R¹⁰)_(r)-phenoxy-, (R¹⁰)_(r)-benzyloxy-, or COOH; each R⁹ is independently H or C₁-C₆-alkyl or, together with the nitrogen atom to which they are attached, form a C₅-C₆-heterocycloalkyl group; each R¹⁰ is independently halo, CN, C₁-C₆-alkyl, C₁-C₆-alkoxy, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, or SO₂CH₃;

Y is O or S; X is NH, N—CH₃, O, or S; Z is —NH— or

m is 0, 1, or 2; each n is independently 0, 1, 2, or 3; and each p is independently 0, 1, 2, or 3.

The method of the present invention provides a way of converting a ketone to a substantially enantiomerically pure chiral compound, which is either useful as a CCR2 modulator or a precursor to a CCR2 modulator.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a method comprising reducing a ketone of formula I:

with an enantioselective hydrogenating agent to form substantially enantiomerically pure alcohol of formula II:

where R—R⁴ and m are as previously defined.

In another aspect, the enantioselective hydrogenating reagent is a bisphosphino-ruthenium or bisphosphino-diamine-ruthenium complex.

In another aspect, the enantioselective hydrogenating reagent is selected from the group consisting of:

In another aspect, R¹ is a BOC or CBz group.

In another aspect, R¹ is

In another aspect, R¹ is

where each R⁵ is independently F, Cl, Br, CF₃, CH₃, benzyloxy, or OCH₃; and n is 0, 1, or 2.

In another aspect, R¹ is:

In another aspect, R¹ is:

wherein each R⁵ is independently F or Cl.

In another aspect, R³ is H and R⁴ is phenyl-(R⁵)_(n), indol-3-yl-(R⁸)_(p), 1-H-pyrrolo[2,3-b]pyridine-3-yl-(R⁸)_(p), benzimidazol-2-yl-(R⁸)_(p), benzoxazol-2-yl-(R⁸)_(p), or pyrazol-3-yl; each R⁸ is independently amino, —NHSO₂CH₃, —NHC(O)CH₃, methyl, methoxy, trifluoromethoxy, benzyloxy, phenoxy, cyano, morpholino, fluoro, or chloro; and p is 0, 1, or 2.

In another aspect, R³ and R⁴, together with the carbon atom to which they are attached, form an optionally substituted spiroindolinyl, a spiroindanyl, a spiroindenyl, or a spirodihydrobenzoxazolyl group.

In another aspect, R³ and R⁴, together with the carbon atom to which they are attached form an optionally substituted spiroindolinyl group optionally substituted with up to two substituents selected from the group consisting of CH₃, F, Cl, and CN.

In another aspect, the present invention is a method comprising reducing a ketone of the following formula:

with an enantioselective ruthenium phosphine hydrogenating agent to form a substantially enantiomerically pure alcohol having the following formula:

wherein R¹ is Cbz or BOC.

In another aspect the ruthenium phosphine hydrogenating agent is

and the reduced compound has the following formula:

or a ditosylate salt thereof.

In another aspect, the reduced compound or ditosylate salt thereof is further reacted with a protic acid to form (1S)-2-(6-chloro-1,2-dihydro-1′H-spiro[indole-3,4′-piperidin]-1′-yl)-1-(4-piperidinyl)ethanol.

In another aspect, the (1S)-2-(6-chloro-1,2-dihydro-1′H-spiro[indole-3,4′-piperidin]-1′-yl)-1-(4-piperidinyl)ethanol is reacted with pentafluorophenyl (2E)-3-(3,5-difluorophenyl)-2-propenoate under such conditions to form (1S)-2-(6-chloro-1,2-dihydro-1′H-spiro[indole-3,4′-piperidin]-1′-yl)-1-{1-[(2E)-3-(3,5-difluorophenyl)-2-propenoyl]-4-piperidinyl}ethanol.

The term “enantioselective hydrogenating agent” refers to a reagent that is used in the hydrogenation process that allows for the production of a substantially enantiomerically pure product, that is, a product that is at least 80%, preferably at least 90%, and most preferably at least 95% enantiomerically pure. Examples of enantioselective hydrogenating agents are bisphosphino-diamine-ruthenium complexes A and B and bisphosphino ruthenium complex C:

Catalyst A is dichloro[(R)-(+)-2,2′,6,6′-tetramethoxy-4,4′-bis(diphenylphosphino)-3,3′-bipyridine][(1R,2R)-(+)-1,2-diphenylethylenediamine]ruthenium(II) Catalyst B is dichloro[(R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl][(1R,2R)-(+)-1,2-diphenylethylenediamine]ruthenium(II) Catalyst C is dichloro[(S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl]ruthenium(II)

The term “amine protecting group” refers to a group that protects the amine to which it is attached against possible competitive reactions. Examples of suitable amine protecting groups include carbobenzyloxy (CBz), t-butoxycarbonyl (BOC), p-methoxybenzylcarbonyl (MOZ), benzyl, p-methoxybenzyl (PMB), and 3,4-dimethoxybenzyl (DMPM). CBz and BOC are particularly suitable.

The symbol:

is used to refer to a substantially enantiomerically pure form (either the S or the R form) of the compound.

As used herein, “C₁-C₆-alkyl” refers to straight or branched hydrocarbon chains containing the specified number of carbon atoms. Examples include methyl, ethyl, n-propyl, n-butyl, isobutyl, isopropyl, t-butyl, and 1,1-dimethylpropyl.

The term “halo” refers to fluoro, chloro, or bromo.

As used herein, “heteroaryl” refers to a 5- or 6-membered aromatic group that contains one or more heteroatoms selected from N, S, and O. Examples of heteroaryl groups include pyridinyl, furyl, thienyl, imidazolyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, and pyrimidinyl groups.

R⁶ and R⁷ may, together with carbon atoms to which they are attached, form a fused benzo group, as illustrated:

Representative examples of C₅-C₆-heterocycloalkyl groups include piperidinyl, piperazinyl, N-methylpiperazinyl, morpholino, and pyrrolidinyl groups. Each R⁹, together with the nitrogen atom to which they are attached, may form such groups.

The following schemes are for illustrative purposes only and are not intended to limit the scope of this invention.

As Scheme 1 illustrates, a compound of formula I containing an amine protecting group such as Cbz can either be a) enantioselectively hydrogenated in a single step or b) deprotected (with a protic acid such as HCl) and coupled with R^(1a)Z (where R^(1a) is a subset of R¹ that excludes an amine protecting group or H; and Z is a suitable leaving group), before undergoing selective hydrogenation.

The following example is for illustrative purposes only and is not intended to limit the scope of the invention.

Preparation of phenylmethyl 4-[(1S)-2-(6-chloro-1,2-dihydro-1′H-spiro[indole-3,4′-piperidin]-1′-yl)-1-hydroxyethyl]-1-piperidinecarboxylate

A. Preparation of phenylmethyl 4-{[dimethyl(oxido)-1⁴-sulfanylidene]acetyl}-1-piperidinecarboxylate

Trimethylsulfoxonium iodide (3.75 g, 17.0 mmol, 2.0 equiv.) and potassium tert-butoxide (2.22 g, 18.8 mmol, 2.2 equiv.) were dissolved in 30 mL of THF and heated to reflux for 3 h. The resultant suspension was cooled to 0° C., whereupon phenylmethyl 4-(chlorocarbonyl)-1-piperidinecarboxylate (2.4 g, 8.5 mmol, 1 equiv.) in 15 mL of THF was added dropwise. The mixture was stirred at 0° C. to room temperature for 3.5 h. CH₂Cl₂ (40 mL) and water (60 mL) were then added. The organic layer was separated, concentrated, and redissolved in 5 mL of refluxing EtOAc. Hexanes (10 mL) was added and the resultant suspension was cooled to room temperature overnight. The product was collected by filtration and dried under vacuum: 2.15 g, 6.37 mmol, 75%. ES-MS: m/z: 338 (M+H⁺). ¹H NMR δ ppm (CDCl₃, 300.13 MHz): 7.26-7.33 (m, 5H), 5.09 (s, 2H), 4.37 (s, 1H), 4.17 (br, 2H), 3.35 (m, 6H), 2.78 (m, 2H), 2.19 (tt, J=11.6, 3.6 Hz, 1H), 1.77 (d, J=12.4 Hz, 2H), 1.52 (ddd, J=24.4, 12.2, 3.6 Hz, 2H). ¹³C NMR δ ppm (CDCl₃, 75.48 MHz): 191.9, 155.0, 136.7, 128.3, 127.7, 127.6, 68.3, 66.8, 46.3, 43.7, 42.0, 28.7.

B. Preparation of phenylmethyl 4-[(6-chloro-1,2-dihydro-1′H-spiro[indole-3,4′-piperidin]-1′-yl)acetyl]-1-piperidinecarboxylate

HCl (4.0 M dioxane solution, 4.90 mL, 19.6 mmol, 1.05 equiv) was added to a suspension of phenylmethyl 4-{[dimethyl(oxido)-1⁴-sulfanylidene]acetyl}-1-piperidinecarboxylate (6.30 g, 18.7 mmol) in THF (60 mL). The mixture was heated to reflux for 6 h, then cooled to room temperature, after which time NaHCO₃ (6.40 g, 76.2 mmol, 4.1 equiv) and 6-chloro-1,2-dihydrospiro[indole-3,4′-piperidine] (3.50 g, 15.7 mmol, 0.84 mmol) were then added. The mixture was heated to reflux for 20 h and cooled to room temperature, EtOAc (45 mL) and water (45 mL) were added, the organic layer separated, washed with NaHCO₃ (sat. aq., 45 mL), and concentrated. The residue was redissolved in EtOAc (30 mL) and added slowly to a solution of TsOH hydrate (6.67 g) in EtOH (6 mL)/EtOAc (30 mL) at reflux. The mixture was cooled to room overnight. The product (bistosylate of phenylmethyl 4-[(6-chloro-1,2-dihydro-1′H-spiro[indole-3,4′-piperidin]-1′-yl)acetyl]-1-piperidinecarboxylate) was collected by filtration and dried under vacuum: 7.52 g, 9.1 mmol, 58%. ES-MS: m/z: 482 (M+H⁺). ¹H NMR δ ppm (DMSO-d6, 300.13 MHz): 9.74 (br, 1H), 7.71 (br, 3H), 7.52 (d, J=8.0 Hz, 4H), 7.29-7.40 (m, 5H), 7.13 (d, J=7.9 Hz, 4H), 7.01-7.17 (m, 3H), 5.08 (s, 2H), 4.53 (br, 2H), 3.98 (m, 2H), 3.65 (s, 2H), 3.41 (d, J=9.9 Hz, 2H), 3.21 (m, 2H), 2.88 (br, 2H), 2.71 (tm, J=11.2 Hz, 1H), 2.29 (s, 6H), 2.19 (m, 2H), 1.84 (d, J=13.6 Hz, 4H), 1.36 (m, 2H).

C. Preparation of phenylmethyl 4-[(1S)-2-(6-chloro-1,2-dihydro-1′H-spiro[indole-3,4′-piperidin]-1′-yl)-1-hydroxyethyl]-1-piperidinecarboxylate

Aqueous NaOH (1 N, 10 mL) was added to a suspension of phenylmethyl 4-[(6-chloro-1,2-dihydro-1′H-spiro[indole-3,4′-piperidin]-1′-yl)acetyl]-1-piperidinecarboxylate bistosylate (672 mg, 0.813 mmol) CH₂Cl₂ (10 mL). The organic layer was washed with another portion of NaOH (1 N, 10 mL), separated, and concentrated. The residue was redissolved in EtOH (6 mL) with KOtBu (18.5 mg, 0.165 mmol, 0.2 equiv.) and added to 16.0 mg of catalyst A (0.017 mmol, 0.02 equiv.) The mixture was hydrogenated (150 psi, 35° C.) for 20 h, after which time the mixture was diluted with CH₂Cl₂ (15 mL) and washed with NaHCO₃ (sat. aq., 15 mL). The organic layer was concentrated, redissolved in 2 mL of EtOAc and added to TsOH hydrate (369.8 mg) in EtOH (0.4 mL)/EtOAc (2 mL) at reflux. The mixture was heated at reflux for 2 h, then cooled to room temperature overnight. The bitosylate of the product was isolated by filtration and dried under vacuum: 492 mg, 0.594 mmol, 73%, 97.3% ee. ES-MS: m/z: 484 (M+H⁺). ¹H NMR δ ppm (DMSO-d6, 300.13 MHz): 9.08 (br, 1H), 7.50 (d, J=8.0 Hz, 4H), 7.29-7.40 (m, 5H), 7.12 (d, J=8.0 Hz, 4H), 7.01 (d, J=7.9 Hz, 1H), 6.83-6.90 (m, 2H), 5.07 (s, 2H), 4.04 (m, 2H), 3.73 (m, 1H), 3.03-3.57 (m, 8H), 2.75 (br, 2H), 2.28 (s, 6H), 2.19 (m, 1H), 1.98 (m, 1H), 1.80 (m, 3H), 1.51 (m, 2H), 1.17 (m, 2H). 

1. A method comprising reducing a ketone of the following formula:

with an enantioselective hydrogenating agent to form a substantially enantiomerically pure alcohol having the following formula:

wherein R is H or OH; R¹ is H, an amine protecting group,

each R² is independently halo, methyl, hydroxy, or hydroxymethyl; R³ is H and R⁴ is phenyl-(R⁵)_(n), indolyl-(R⁸)_(p), 1-H-pyrrolo[2,3-b]pyridine-3-yl-(R⁸)_(p), benzimidazolyl-(R⁸)_(p), benzoxazolyl-(R⁸)_(p), or pyrazolyl; or R³ and R⁴, together with the carbon atom to which they are attached form a spiroindolinyl, a spiroindanyl, a spiroindenyl, or a spirodihydrobenzoxazolyl group, each optionally substituted with up to three substituents selected from the group consisting of halo, CN, C₁-C₆-alkyl, C₁-C₆-alkoxy, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, SO₂CH₃, (R⁵)_(n)-phenoxy-, (R⁵)_(n)-benzyloxy-, C(O)N(R⁹)₂, and COOH; each R⁵ is independently halo, CN, C₁-C₆-alkyl, C₁-C₆-alkoxy, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, SO₂CH₃, phenyl, C(O)N(R⁹)₂, or COOH; R⁶ and R⁷ are each independently H, C₁-C₆ alkyl, phenyl-(R⁵)_(n), heteroaryl-(R⁸)_(p), CON(R⁹)₂, CN, COOH, COOCH₃, COOCH₂CH₃, or R⁶ and R⁷, together with the carbon atoms to which they are attached, form a fused benzo group; each R⁸ is independently halo, amino, cyano, C₁-C₆-alkyl, C₁-C₆-alkoxy, —NHSO₂CH₃, —NHC(O)CH₃, C₅-C₆-heterocycloalkyl, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, SO₂CH₃, C(O)N(R¹⁰)₂, (R¹⁰)_(r)-phenoxy-, (R¹⁰)_(r)-benzyloxy-, or COOH; each R⁹ is independently H or C₁-C₆-alkyl or, together with the nitrogen atom to which they are attached, form a C₅-C₆-heterocycloalkyl group; each R¹⁰ is independently halo, CN, C₁-C₆-alkyl, C₁-C₆-alkoxy, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, or SO₂CH₃; Y is O or S; X is NH, N—CH₃, O, or S; Z is —NH— or

m is 0, 1, or 2; each n is independently 0, 1, 2, or 3; and each p is independently 0, 1, 2, or
 3. 2. The method of claim 1 wherein the enantioselective hydrogenating reagent is a bisphosphino-ruthenium or bisphosphino-diamine-ruthenium complex.
 3. The method of claim 1 wherein the enantioselective hydrogenating reagent is selected from the group consisting of:


4. The method of claim 1 wherein R¹ is a BOC or Cbz group.
 5. The method of claim 1 wherein R¹ is:


6. The method of claim 5 wherein R¹ is:

where each R⁵ is independently F, Cl, Br, CF₃, CH₃, benzyloxy, or OCH₃; and n is 0, 1, or
 2. 7. The method of claim 1 wherein R¹ is:


8. The method of claim 1 wherein R¹ is:

wherein each R⁵ is independently F or Cl.
 9. The method of claim 1 wherein R³ is H and R⁴ is phenyl-(R⁵)_(n), indol-3-yl-(R⁸)_(p), 1-H-pyrrolo[2,3-b]pyridine-3-yl-(R⁸)_(p), benzimidazol-2-yl-(R⁸)_(p), benzoxazol-2-yl-(R⁸)_(p), or pyrazol-3-yl; each R⁸ is independently amino, —NHSO₂CH₃, —NHC(O)CH₃, methyl, methoxy, trifluoromethoxy, benzyloxy, phenoxy, cyano, morpholino, fluoro, or chloro; and p is 0, 1, or
 2. 10. The method of claim 1 wherein R³ and R⁴, together with the carbon atom to which they are attached, form an optionally substituted spiroindolinyl, a spiroindanyl, a spiroindenyl, or a spirodihydrobenzoxazolyl group.
 11. The method of claim 10 wherein R³ and R⁴, together with the carbon atom to which they are attached, form an optionally substituted spiroindolinyl group optionally substituted with up to two substituents selected from the group consisting of CH₃, F, Cl, and CN.
 12. A method comprising reducing a ketone of the following formula:

with an enantioselective ruthenium phosphine hydrogenating agent to form a substantially enantiomerically pure alcohol having the following formula:

wherein R¹ is Cbz or BOC.
 13. The method of claim 12 wherein the ruthenium phosphine hydrogenating agent is

and the reduced compound has the following formula:

or a ditosylate salt thereof.
 14. The method of claim 13 wherein the reduced compound or ditosylate salt thereof is further reacted with a protic acid to form (1S)-2-(6-chloro-1,2-dihydro-1′H-spiro[indole-3,4′-piperidin]-1′-yl)-1-(4-piperidinyl)ethanol.
 15. The method of claim 14 wherein the (1S)-2-(6-chloro-1,2-dihydro-1′H-spiro[indole-3,4′-piperidin]-1′-yl)-1-(4-piperidinyl)ethanol is reacted with pentafluorophenyl (2E)-3-(3,5-difluorophenyl)-2-propenoate under such conditions to form (1S)-2-(6-chloro-1,2-dihydro-1′H-spiro[indole-3,4′-piperidin]-1′-yl)-1-{1-[(2E)-3-(3,5-difluorophenyl)-2-propenoyl]-4-piperidinyl}ethanol. 